CN108472261B - Apixaban solid composition and preparation method thereof - Google Patents

Apixaban solid composition and preparation method thereof Download PDF

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Publication number
CN108472261B
CN108472261B CN201780005318.0A CN201780005318A CN108472261B CN 108472261 B CN108472261 B CN 108472261B CN 201780005318 A CN201780005318 A CN 201780005318A CN 108472261 B CN108472261 B CN 108472261B
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apixaban
solid composition
binder
content
povidone
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CN108472261A (en
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黄启彪
黄心
黄芳芳
游劲松
赵锋
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Guangdong HEC Pharmaceutical
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Sunshine Lake Pharma Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2893—Tablet coating processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Abstract

The invention provides an apixaban solid composition and a preparation method thereof90Greater than 89 μm.

Description

Apixaban solid composition and preparation method thereof
PRIORITY INFORMATION
The present application requests priority and benefit of patent applications No. 201610018516.8, 201610018594.8 filed 2016, 12.01.12.8.8.3532 from the chinese intellectual property office, and is hereby incorporated by reference in its entirety.
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to an apixaban solid composition and a preparation method thereof.
Background
Apixaban (API) is a known compound having the following structure:
Figure GPA0000246715480000021
the chemical name of apixaban is 4, 5, 6, 7-tetrahydro-1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-piperidin-1-yl) phenyl ] -1H-pyrazolo [3, 4-c ] pyridine-3-carboxamide (CAS name) or 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl ] -4, 5, 6, 7-tetrahydro-1H-pyrazolo [3, 4-c ] pyridine-3-carboxamide (IUPAC name).
Apixaban is disclosed in U.S. patent 6,967,208 and U.S. patent application publications 2012/0087978 and 2013/0045245, the entire contents of which are incorporated by reference into this application. Apixaban has utility as a factor Xa inhibitor, developed for oral administration for a variety of indications requiring the use of antithrombotic agents, such as the prevention of stroke in patients after hip or knee surgery and in atrial fibrillation, or for the treatment of venous thrombosis.
Currently, the following are common methods used in the pharmaceutical field to improve drug stability and dissolution rate: salifying, reducing the particle size of the medicine, preparing into emulsion or self-microemulsion by adopting a non-aqueous solvent/cosolvent, clathrating by cyclodextrin, and preparing into thermodynamically unstable crystal form or solid dispersion and the like.
However, the pharmaceutical composition and the preparation method of apixaban formulations remain to be further investigated.
Disclosure of Invention
The present application is based on the discovery by the inventors of the following problems and facts:
the Apixaban tablets in the current market have high manufacturing cost of production equipment, large loss of compressibility of materials, great risk on uniformity of products and poor compressibility of particles. According to the us patent application publication 2013/0045245, it is reported that formulations prepared using wet granulation processes as well as formulations prepared using large particles of apixaban drug give non-optimal in vivo absorption, which can create quality control challenges, and therefore, itD with less than 89 microns was developed90(90% by volume) apixaban granules, which indicates that the pharmaceutical preparation has high requirements on raw materials, and the production process of the raw material medicaments is more complicated.
The present invention provides a novel apixaban solid composition and a process for producing the solid composition. The inventor surprisingly finds that the apixaban solid composition provided by the application has faster dissolution rate and higher dissolution rate compared with the prior art, and the product stability is higher, and simultaneously, the inventor finds that the method for producing the apixaban solid composition is simple to operate, reliable in quality and more suitable for commercial production.
Based on this, in a first aspect of the invention, the invention proposes a solid composition of apixaban. According to an embodiment of the invention, the solid composition comprises apixaban having a particle size D90Greater than 89 μm. The inventors have surprisingly found that the particle size D of apixaban90Larger than 89 mu m, can greatly overcome the limit of the small-particle-size Apixaban on the scale production, greatly reduce the production cost and is suitable for industrial production. The apixaban solid composition has good granulation property and compressibility, stable and controllable tabletting process and high process repeatability. More importantly, the solid composition of apixaban provided by the embodiment of the invention has the remarkable advantages of higher dissolution rate and higher dissolution rate compared with the existing apixaban preparation, and higher stability of the product.
According to an embodiment of the present invention, the above solid composition of apixaban may further have at least one of the following additional technical features:
according to an embodiment of the present invention, the solid composition of apixaban is obtained by wet granulation. The inventors found that the particle diameter D90The Apixaban with the particle size of more than 89 mu m is matched with a wet granulation process, so that the solid composition has better granulability and compressibility, higher dissolution rate and higher stability.
According to an embodiment of the present invention, the solid composition of apixaban further comprises a binder. The inventor finds that the solid composition of apixaban has better particle forming property and compressibility and higher process reproducibility by matching with the binder.
Particle size D of Apixaban according to an embodiment of the invention90Greater than 89 μm. For example, according to a specific embodiment of the present invention, the particle size D of apixaban90May be no less than 90 microns, preferably no less than 100 microns, more preferably no less than 150 microns, and further, according to embodiments of the present invention, the particle size D of apixaban90May be no greater than 550 microns, preferably no greater than 400 microns.
According to an embodiment of the invention, the particle size D of the apixaban90Not less than 100 μm and not more than 550 μm. The inventors found that the particle size D of apixaban90The thickness of the solid composition is not less than 100 mu m and not more than 550 mu m, and the solid composition of apixaban provided by the embodiment of the invention has higher dissolution rate and dissolution degree and higher product stability by matching with the action of a binder.
According to an embodiment of the invention, the particle size D of the apixaban90Not less than 150 μm and not more than 400 μm. The inventors found that the particle size D of apixaban90The thickness of the solid composition is not less than 150 mu m and not more than 400 mu m, and the solid composition of apixaban provided by the embodiment of the invention has higher dissolution rate and dissolution degree and higher product stability by matching with the action of a binder.
According to an embodiment of the invention, the binder is povidone. The inventor finds that the povidone serving as the adhesive has better granulation property and compressibility, stable and controllable tabletting process, better process reproducibility and more stable process.
According to an embodiment of the invention, the binder is present in an amount of 2.00% to 8.00% based on the total weight of the solid composition. The inventor finds that the dosage of the binder in the solid composition is controlled to be 2.00-8.00%, the dissolution of the product is faster and the dissolution platform is normal.
According to an embodiment of the invention, the binder is provided in a form dissolved in an acidic substance or DMSO. The inventor finds out through screening experiments that the adhesive is provided in a form of being dissolved in an acidic substance or DMSO, and is more beneficial to the dissolution of the solid composition of apixaban.
According to an embodiment of the invention, the acidic substance is acetic acid. The inventors have found that the dissolution rate of the solid composition of apixaban has a significant advantage when the binder is provided in a form dissolved in acetic acid.
According to the embodiment of the invention, the content of the adhesive in the acetic acid is 0.02g/mL-0.5 g/mL. The inventors found that when the binder is present in glacial acetic acid in an amount in the range of 0.02g/mL to 0.5g/mL, the product dissolves faster and the dissolution plateau is normal.
According to a specific embodiment of the present invention, the apixaban solid composition further comprises a filler, a disintegrant, a surfactant and a lubricant. The inventors have surprisingly found that the particle size D of apixaban90More than 89 mu m, can greatly overcome the limit of the apixaban with small grain diameter to the scale production, and further match the action of the filling agent, the disintegrating agent, the surfactant and the lubricant while matching the adhesive, so that the granulation property and the compressibility of the granules are further improved, and the stability, the dissolution rate and the dissolution rate of the obtained composition are further improved.
According to a specific embodiment of the present invention, the filler is corn starch, pregelatinized starch, complex starch, anhydrous lactose, lactose monohydrate, microcrystalline cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, mannitol, maltitol, inositol, xylitol, lactitol, or any combination thereof.
According to a particular embodiment of the invention, the filler is a mixture of anhydrous lactose and microcrystalline cellulose.
According to still another embodiment of the present invention, the content of the anhydrous lactose is 33.50% -63.50% and the content of the microcrystalline cellulose is 24.00% -54.00% based on the total weight of the solid composition.
According to a particular embodiment of the invention, the disintegrant is croscarmellose sodium.
According to still another embodiment of the present invention, the content of the disintegrant is 2.00% to 8.00% based on the total weight of the solid composition.
According to a particular embodiment of the invention, the surfactant is sodium lauryl sulfate,
according to a further embodiment of the present invention, the surfactant is present in an amount of 0.50% to 4.00% based on the total weight of the solid composition.
According to a particular embodiment of the invention, the lubricant is magnesium stearate.
According to still another embodiment of the present invention, the lubricant is present in an amount of 0.50% to 2.50% based on the total weight of the solid composition.
In a second aspect of the invention, the invention proposes a solid composition of apixaban. According to an embodiment of the invention, the solid composition comprises: 2.50 parts by weight of apixaban, 33.50-63.50 parts by weight of anhydrous lactose, 24.00-54.00 parts by weight of microcrystalline cellulose, 2.00-8.00 parts by weight of croscarmellose sodium, 2.00-8.00 parts by weight of povidone, 0.50-4.00 parts by weight of sodium lauryl sulfate and 0.50-2.50 parts by weight of magnesium stearate, wherein the particle size D of the apixaban is90Greater than 89 μm. The apixaban solid composition provided by the embodiment of the invention can greatly overcome the limitation of small-particle size apixaban on scale production, and 2.50% of apixaban is simultaneously matched with the functions of the filler, the disintegrant, the binder, the surfactant and the lubricant in the proportion, especially the function of the binder, so that the granulation property and the compressibility of the granules are better, the tabletting process is stable and controllable, and the process repeatability is higher. The apixaban solid composition provided by the embodiment of the invention has the obvious advantages of simple preparation process, suitability for mass production, higher dissolution rate and higher dissolution rate compared with the existing apixaban preparation, and higher product stability.
According to an embodiment of the present invention, the above solid composition of apixaban may further have at least one of the following additional technical features:
according to an embodiment of the invention, the particle size D90 of apixaban is not less than 100 μm and not more than 550 μm. The inventors found that the particle size D of apixaban90Is not smallThe solid composition of apixaban in the invention embodiment has higher dissolution rate and higher product stability by combining the combined action of the filler, the disintegrant, the binder, the surfactant and the lubricant with the above dosage, especially the action of the binder with the above dosage in the range of 100-550 μm.
According to an embodiment of the invention, the particle size D90 of apixaban is not less than 150 μm and not more than 400 μm. The inventors found that the particle size D of apixaban90The particle size is not less than 150 mu m and not more than 400 mu m, and the solid composition of apixaban in the embodiment of the invention has higher dissolution rate and higher product stability by combining the combined action of the filler, the disintegrant, the binder, the surfactant and the lubricant with the dosage, particularly the action of the binder with the dosage.
In a third aspect of the invention, the invention proposes a solid composition of apixaban. According to an embodiment of the present invention, the solid composition comprises, based on the total weight of the solid composition: 2.50% apixaban, 48.50% anhydrous lactose, 39.00% microcrystalline cellulose, 4.00% croscarmellose sodium, 3.00% povidone, 2.00% sodium lauryl sulfate and 1.00% magnesium stearate, the particle size D of the apixaban90Greater than 89 μm.
In a fourth aspect of the invention, the invention proposes a solid composition of apixaban. According to a particular embodiment of the invention, the solid composition comprises, based on the total weight of the solid composition: 2.50% apixaban, 63.50% anhydrous lactose, 24.00% microcrystalline cellulose, 4.00% croscarmellose sodium, 3.00% povidone, 2.00% sodium lauryl sulfate and 1.00% magnesium stearate, the particle size D of the apixaban90Greater than 89 μm.
In a fifth aspect of the invention, the invention proposes a solid composition of apixaban. According to a particular embodiment of the invention, the solid composition comprises, based on the total weight of the solid composition: 2.50% apixaban, 33.50% lactose anhydrous, 54.00% microcrystalline cellulose, 4.00% croscarmellose sodium, 3.00% croscarmellose sodium% povidone, 2.00% sodium lauryl sulfate and 1.00% magnesium stearate, particle size D of the apixaban90Greater than 89 μm.
In a sixth aspect of the invention, the invention provides a solid composition of apixaban. According to a particular embodiment of the invention, the solid composition comprises, based on the total weight of the solid composition: apixaban 2.50%, anhydrous lactose 47.50%, microcrystalline cellulose 39.00%, croscarmellose sodium 2.00%, povidone 8.00%, sodium lauryl sulfate 0.50% and magnesium stearate 0.50%, wherein particle size D of Apixaban is90Greater than 89 μm.
In a seventh aspect of the invention, the invention provides a solid composition of apixaban. According to a particular embodiment of the invention, the solid composition comprises, based on the total weight of the solid composition: 2.50% apixaban, 42.00% anhydrous lactose, 39.00% microcrystalline cellulose, 8.00% croscarmellose sodium, 2.00% povidone, 4.00% sodium lauryl sulfate and 2.50% magnesium stearate, the particle size D of the apixaban90Greater than 89 μm.
The apixaban solid composition according to the embodiment of the invention has the remarkable advantages of higher dissolution rate and higher product stability compared with the prior art.
According to a specific embodiment of the present invention, the solid composition may be a tablet, a capsule or a granule. The preparation form is beneficial to the dissolution of the solid composition in the body of a patient and the absorption of the active ingredients.
In an eighth aspect of the invention, the invention proposes a process for the preparation of an apixaban composition. According to an embodiment of the invention, the method comprises: subjecting apixaban to a wet granulation process in order to obtain a binder solution, said apixaban having a particle size D90Greater than 89 μm. The apixaban composition prepared by the method provided by the embodiment of the invention can greatly overcome the limitation of small-particle size apixaban on large-scale production, is more suitable for industrial large-scale production, and has better particle granulability and compressibility and stable tabletting processThe method has the advantages of controllable quality, good process reproducibility and more stable process. The apixaban composition prepared by the method provided by the embodiment of the invention has the remarkable advantages of higher dissolution rate and dissolution rate compared with the existing apixaban preparation, and higher stability of the product.
According to an embodiment of the present invention, the above method for preparing apixaban compositions may further comprise at least one of the following additional technical features:
according to an embodiment of the present invention, the wet granulation is performed by: apixaban and the binder are dissolved in a wetting agent in order to obtain a binder solution. The inventor finds that the solid composition of apixaban obtained by wet granulation and the binding agent have better granulation performance and compressibility and higher process reproducibility.
According to an embodiment of the invention, the wetting agent is acetic acid or DMSO. The inventor finds out through screening experiments that the wetting agent is acetic acid or DMSO, and the dissolution rate of the obtained solid composition of apixaban is higher.
According to an embodiment of the invention, the binder is povidone. The inventor finds that the povidone serving as the adhesive has better granulation property and compressibility, stable and controllable tabletting process, better process reproducibility and more stable process.
According to an embodiment of the invention, the particle size D of the apixaban90Not less than 100 μm and not more than 550 μm. The inventors found that the particle diameter D is adjusted90The Apixaban and the binder with the particle size of not less than 100 mu m and not more than 550 mu m are dissolved in the wetting agent, the obtained solid composition has higher dissolution rate and dissolution degree, and the product has higher stability.
According to an embodiment of the invention, the particle size D of the apixaban90Not less than 150 μm and not more than 400 μm. The inventors found that the particle diameter D is adjusted90The Apixaban and the binder with the particle size of not less than 150 mu m and not more than 400 mu m are dissolved in the wetting agent, the obtained solid composition has higher dissolution rate and dissolution degree, and the product has higher stability.
According to an embodiment of the invention, the content of the binder in the wetting agent is 0.02g/mL to 0.5 g/mL. The inventors have found that when the binder is present in the humectant in an amount in the range of 0.02g/mL to 0.5g/mL, the product dissolves more quickly and the dissolution plateau is normal.
According to a specific embodiment of the present invention, the method for preparing the apixaban composition further comprises: adding the filler, the disintegrant and the surfactant into a fluidized bed and carrying out preheating treatment; spraying the binder solution into the pre-heat treated product; subjecting the pre-heat-treated product sprayed with the binder solution to a drying treatment so as to obtain dry particles; subjecting the dry granules to a size reduction treatment; and adding a lubricant to the granules obtained after the size stabilization and carrying out a total mixing treatment. The inventor finds that by utilizing the process for preparing the apixaban composition, compared with a dry granulation process, the obtained product has higher dissolution rate and higher dissolution rate, and the product quality is improved.
According to a further embodiment of the invention, the temperature after the preheating treatment is between 35 ℃ and 50 ℃. The inventors have found that the spraying is carried out under the above conditions, and the uniformity and compressibility of the granules can be further ensured. The inventor discovers through practical investigation that the temperature after preheating treatment is lower than 35 ℃, the material is too wet and easy to collapse; when the temperature is higher than 50 ℃, the amount of fine powder is too large, and the compressibility is deteriorated.
According to a further embodiment of the invention, the spraying is carried out at an atomization pressure of 0.5-2.0bar and a spraying velocity of 3.0-20.0 g/min. The inventors have found that the spraying is carried out under the above conditions, and the uniformity and compressibility of the granules can be further ensured. The inventor discovers through practical investigation that the atomization pressure is higher than 2.0bar, so that spray drying is easily caused, the granulation property is deteriorated, and irregular fluidization of materials is caused; the atomization pressure is lower than 0.5bar, the liquid drop is too large, and the prepared particles are coarser; the spraying speed is higher than 20.0g/min, the materials are over-wet, the prepared particles are coarser, and the bed collapse is easy to occur; the spraying speed is lower than 3.0g/min, spray drying can be caused, and the amount of the prepared fine powder is also larger.
According to a specific embodiment of the present invention, the method for preparing the apixaban composition further comprises: adding the filler, the disintegrant and the surfactant into a high-shear wet granulator and performing premixing treatment; spraying the binder solution into the pre-mixed treated product so as to obtain wet granules; adding the wet granules into a fluidized bed for drying treatment so as to obtain dry granules; subjecting the dry granules to a size reduction treatment; and adding a lubricant to the granules obtained after the size stabilization and carrying out a total mixing treatment. The inventor finds that by utilizing the process for preparing the apixaban composition, compared with a dry granulation process, the obtained product has higher dissolution rate and higher dissolution rate, and the product quality is improved.
According to still another embodiment of the present invention, the spraying is performed at a spraying speed of 5 to 60 g/min. The inventor finds that the liquid spraying speed is higher than 60g/min, the liquid adding is too fast, the material is easy to agglomerate under the action of the adhesive, the coarse particles are too much after drying, the compressibility is poor, and the content uniformity of the finished product is influenced; and the liquid spraying speed is lower than 5g/min, liquid adding is too slow, the wettability of materials is influenced, so that more fine particle powder is prepared, the compressibility is poor, the content uniformity of a finished product is influenced, and meanwhile, the liquid spraying speed is too slow, the liquid adding time is prolonged, and the production efficiency is influenced. Therefore, the spraying speed is controlled to be 5-60 g/min, the granulation property and the compressibility can be further improved, and the granulation efficiency can be further improved.
According to an embodiment of the present invention, the method may further comprise tabletting and coating the product after the total blending process. The tabletting treatment can avoid the composition from contacting with the stomach and intestine immediately to reduce the drug effect, and the coating treatment can effectively isolate the composition from air, prevent moisture and light, and further improve the stability of the product.
In a ninth aspect of the invention, the invention proposes a process for the preparation of an apixaban composition. According to an embodiment of the invention, the method comprises: (1) dissolving apixaban and a binder in a wetting agent in order to obtain a binder solution, said apixaban having a particle size D90More than 89 μm, the wetting agent is acetic acid or DMSO, the adhesive is povidone, and the content of the adhesive in the wetting agent is 0.02g/mL-0.5 g/mL;(2) adding the filler, the disintegrant and the surfactant into a fluidized bed, and preheating, wherein the temperature is 35-50 ℃ after preheating; (3) spraying the binder solution into the pre-heat-treated product under conditions of an atomization pressure of 0.5 to 2.0bar and a liquid spraying speed of 3.0 to 20.0g/min, and drying the pre-heat-treated product sprayed with the binder solution to obtain dry particles; (4) subjecting the dry granules to a size reduction treatment; (5) adding a lubricant into the granules obtained after the size stabilization and carrying out total mixing treatment; and (6) tabletting and coating the product after the total mixing treatment. The apixaban composition prepared by the method provided by the embodiment of the invention can greatly overcome the limitation of small-particle size apixaban on scale production, is more suitable for industrial scale production, and has better particle graining property and compressibility, stable and controllable tabletting process, good process reproducibility and more stable process. The apixaban composition prepared by the method provided by the embodiment of the invention has the remarkable advantages of higher dissolution rate and dissolution rate compared with the existing apixaban preparation, and higher stability of the product.
In a tenth aspect of the invention, the invention proposes a process for the preparation of an apixaban composition. According to an embodiment of the invention, the method comprises: (1) dissolving apixaban and a binder in a wetting agent in order to obtain a binder solution, said apixaban having a particle size D90More than 89 μm, the wetting agent is acetic acid or DMSO, the adhesive is povidone, and the content of the adhesive in the wetting agent is 0.02g/mL-0.5 g/mL; (2) adding the filler, the disintegrant and the surfactant into a high-shear wet granulator and performing premixing treatment; (3) spraying the binder solution into the product after the premixing treatment, wherein the spraying is carried out at the spraying speed of 5-60 g/min, and granulating the product after the premixing treatment sprayed with the binder solution, wherein the plasmid treatment time is 3-5 min, so as to obtain wet granules; (4) adding the wet granules into a fluidized bed for drying treatment so as to obtain dry granules; (5) subjecting the dry granules to a size reduction treatment; (6) adding lubricant to the granules obtained after the size stabilization and carrying outPerforming total mixing treatment; and (7) tabletting and coating the product after the total mixing treatment. The apixaban composition prepared by the method provided by the embodiment of the invention can greatly overcome the limitation of small-particle size apixaban on scale production, is more suitable for industrial scale production, and has better particle graining property and compressibility, stable and controllable tabletting process, good process reproducibility and more stable process. The apixaban composition prepared by the method provided by the embodiment of the invention has the remarkable advantages of higher dissolution rate and dissolution rate compared with the existing apixaban preparation, and higher stability of the product.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The term "comprising" or "comprises" is open-ended, i.e. comprising what is specified in the present invention, but not excluding other aspects.
In the context of the present invention, all numbers disclosed herein are approximate values, regardless of whether the word "about" or "approximately" is used. There may be differences below 10% in the value of each number or reasonably considered by those skilled in the art, such as differences of 1%, 2%, 3%, 4% or 5%.
D90That is, the 90% cumulative particle size volume distribution number means the particle size corresponding to 90% of the cumulative particle size volume distribution number of a sample, or less than D90The particle volume of this value represents 90% of the total particle volume. The particle size (particle size) distribution of the particles of the present invention can be determined by laser diffraction. In the following examples, the particle size (particle size) distribution of apixaban drug substance was measured using a Malvern laser particle size analyzer model Mastersizer 2000. When the measurement is carried out,and (3) taking a proper amount of a sample to be tested into an automatic dry-method sample injector, carrying out parallel measurement for 3 times, and averaging the results.
Solid composition of apixaban
In one aspect, the present invention provides a pharmaceutical composition of apixaban comprising apixaban and optionally a filler, a disintegrant, a binder, a surfactant and a lubricant, wherein the particle size D of apixaban is90Greater than 89 μm. The inventors have surprisingly found that the particle size D of apixaban90Larger than 89 mu m, can greatly overcome the limit of the small-particle size Apixaban on the scale production, and simultaneously, under the action of the adhesive, the granule forming property and the compressibility are better, the tabletting process is stable and controllable, and the process reproducibility is higher. More importantly, the solid composition of apixaban provided by the embodiment of the invention has the remarkable advantages of higher dissolution rate and higher dissolution rate compared with the existing apixaban preparation, and higher stability of the product.
According to an embodiment of the invention, wherein the particle size D of the active ingredient apixaban90Greater than 89 μm. In one embodiment, the particle size D of the active ingredient apixaban90100 μm or more and 550 μm or less. In another embodiment, the particle size D of the active ingredient apixaban90150 μm or more and not more than 400 μm. In a further embodiment, the particle size D of the active ingredient apixaban90Equal to 100 μm, 150 μm, 200 μm or 300 μm.
According to a specific embodiment of the present invention, the apixaban solid composition further comprises a filler, a disintegrant, a surfactant and a lubricant.
In one embodiment, the filler is corn starch, pregelatinized starch, complex starch, anhydrous lactose, lactose monohydrate, microcrystalline cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, mannitol, maltitol, inositol, xylitol, lactitol, or any combination thereof. A mixture of anhydrous lactose and microcrystalline cellulose is preferred. More preferably a mixture of anhydrous lactose DCL-21AN and microcrystalline cellulose PH 101. Wherein, when the content of the anhydrous lactose is 33.50 to 63.50 percent and the content of the microcrystalline cellulose is 24.00 to 54.00 percent, the quality of the product is optimal.
In another embodiment, the binder is pregelatinized gelatin, povidone, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, powdered sugar, starch slurry, gelatin, or any combination thereof. Povidone is preferred. More preferably povidone K29/32. Wherein, when the content of the adhesive is 2.00-8.00% by weight, the quality of the product is optimal.
In another embodiment, the disintegrant is sodium carboxymethyl starch, crospovidone, croscarmellose sodium, sodium cross-linked carboxymethyl starch, low substituted hydroxypropyl cellulose, or any combination thereof. Croscarmellose sodium is preferred. Wherein, when the content of the disintegrating agent is 2.00-8.00% by weight, the quality of the product is optimal.
In another embodiment, the surfactant is sodium lauryl sulfate, tween, span, or any combination thereof. Sodium lauryl sulfate is preferred. Wherein, when the content of the surfactant is 0.50 to 4.00 percent by weight, the product is optimal.
In another embodiment, the lubricant is stearic acid, magnesium stearate, calcium stearate, zinc stearate, glyceryl palmitostearate, sodium stearyl fumarate, canola oil, hydrogenated vegetable oil, mineral oil sodium lauryl sulfate, magnesium oxide, aerosil, silicone oil, polyethylene glycol, polyvinyl alcohol, sodium phenyl ate, talc, or any combination thereof. Magnesium stearate is preferred. Wherein, when the content of the lubricant is 0.50 to 2.50 percent by weight, the product is optimal.
In another aspect, the present invention provides a solid composition of apixaban, comprising: 2.50 parts by weight of apixaban, 33.50-63.50 parts by weight of anhydrous lactose, 24.00-54.00 parts by weight of microcrystalline cellulose, 2.00-8.00 parts by weight of croscarmellose sodium, 2.00-8.00 parts by weight of povidone, 0.50-4.00 parts by weight of dodecaneSodium thiosulfate; 0.50-2.50 parts by weight of magnesium stearate, wherein the particle size D of the apixaban90Greater than 89 μm. In other words, the solid composition of apixaban comprises 2.50% of apixaban, 33.50-63.50% of lactose anhydrous, 24.00-54.00% of microcrystalline cellulose, 2.00-8.00% of croscarmellose sodium, 2.00-8.00% of povidone, 0.50-4.00% of sodium lauryl sulfate and 0.50-2.50% of magnesium stearate, calculated as weight percentages, based on the total weight of the solid composition of apixaban, wherein the particle size D of apixaban is90Greater than 89 μm.
In one embodiment, the solid composition comprises apixaban 2.50%, anhydrous lactose 48.50%, microcrystalline cellulose 39.00%, croscarmellose sodium 4.00%, povidone 3.00%, sodium lauryl sulfate 2.00%, and magnesium stearate 1.00%.
In another embodiment, the solid composition comprises apixaban 2.50%, lactose anhydrous 63.50%, microcrystalline cellulose 24.00%, croscarmellose sodium 4.00%, povidone 3.00%, sodium lauryl sulfate 2.00%, and magnesium stearate 1.00%.
In another embodiment, the solid composition comprises apixaban 2.50%, lactose anhydrous 33.50%, microcrystalline cellulose 54.00%, croscarmellose sodium 4.00%, povidone 3.00%, sodium lauryl sulfate 2.00%, and magnesium stearate 1.00%.
In another embodiment, the solid composition comprises apixaban 2.50%, anhydrous lactose 47.50%, microcrystalline cellulose 39.00%, croscarmellose sodium 2.00%, povidone 8.00%, sodium lauryl sulfate 0.50%, and magnesium stearate 0.50%.
In another embodiment, the solid composition comprises apixaban 2.50%, lactose anhydrous 42.00%, microcrystalline cellulose 39.00%, croscarmellose sodium 8.00%, povidone 2.00%, sodium lauryl sulfate 4.00%, and magnesium stearate 2.50%.
The Apixaban solid composition provided by the invention is in the form of tablets, capsules or granules.
The apixaban solid composition provided by the invention has good stability and content uniformity, and effectively improves the medication safety; the dissolution rate is high, and the dissolution and the absorption in the body of the medicine can be effectively increased.
The apixaban solid composition provided by the invention is different from preparations of original research or other pharmaceutical imitation companies, and has a particle size range of more than 89 mu m for raw material medicines, so that the limitation of small-particle size apixaban on scale production can be greatly overcome, the production process of the raw material medicines can be simplified, and the apixaban solid composition is more suitable for commercial production.
Process for preparing apixaban compositions
In yet another aspect, the present invention provides a method of preparing an apixaban composition. According to an embodiment of the invention, the method comprises: carrying out wet granulation on apixaban, wherein the particle size D of the apixaban90Greater than 89 μm. According to a particular embodiment of the invention, the wet granulation is carried out by: apixaban and the binder are dissolved in a wetting agent in order to obtain a binder solution. The apixaban composition prepared by the method provided by the embodiment of the invention can greatly overcome the limitation of small-particle size apixaban on scale production, is more suitable for industrial scale production, and has better particle graining property and compressibility, stable and controllable tabletting process, good process reproducibility and more stable process. The apixaban composition prepared by the method provided by the embodiment of the invention has the remarkable advantages of higher dissolution rate and dissolution rate compared with the existing apixaban preparation, and higher stability of the product.
In a specific embodiment, the wetting agent is acetic acid or DMSO. In another embodiment, the binder may be povidone.
In another embodiment, the ratio of the binder to the wetting agent is from 0.02g/mL to 0.5 g/mL.
Further, the method of the invention comprises the following steps:
(1) dissolving apixaban and a binding agent in a wetting agent to prepare a binding agent solution;
(2) adding the filler, the disintegrant and the surfactant into a fluidized bed for preheating, spraying the binder solution after the preset material temperature is reached, and drying after the spraying is finished to obtain dry particles;
(3) granulating the obtained dry particles;
(4) adding lubricant, and mixing the granules.
In one embodiment, in step (2), the temperature of the material is from 35 ℃ to 50 ℃.
In another embodiment, in step (2), the atomization pressure is adjusted to 0.5 to 2.0bar and the liquid injection rate is adjusted to 3.0 to 20.0 g/min.
In another embodiment, step (2) may be replaced with:
(2-1) adding a filler, a disintegrant and a surfactant into a high-shear wet granulator for premixing, and then spraying the binder solution to prepare wet granules;
(2-2) adding the wet granules into a fluidized bed for drying.
Further, the method of the present invention comprises two steps of (5) tabletting and (6) coating.
Wherein, in another embodiment, the filler is corn starch, pregelatinized starch, complex starch, anhydrous lactose, lactose monohydrate, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, mannitol, maltitol, inositol, xylitol, lactitol, or any combination thereof.
In another embodiment, the disintegrant is sodium carboxymethyl starch, crospovidone, croscarmellose sodium, sodium cross-linked carboxymethyl starch, low substituted hydroxypropyl cellulose, or any combination thereof.
In another embodiment, the surfactant is sodium lauryl sulfate, tween, span, or any combination thereof.
In another embodiment, the lubricant is stearic acid, magnesium stearate, calcium stearate, zinc stearate, glyceryl palmitostearate, sodium stearyl fumarate, canola oil, hydrogenated vegetable oil, mineral oil sodium lauryl sulfate, magnesium oxide, aerosil, silicone oil, polyethylene glycol, polyvinyl alcohol, sodium phenyl ate, talc, or any combination thereof.
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. In the examples described below, all temperatures are given in degrees Celsius unless otherwise indicated. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
The following shorthand words are used throughout the present invention
g
mL of
Microliter of μ L
h hours
min for
s second
In examples 1 to 5, the contents of the respective components of formulas 1 to 13 are shown in Table 1.
Table 1:
Figure GPA0000246715480000121
EXAMPLE 1 examination of the granulation Process
In this example, the inventors measured the particle size D of apixaban90At 300 microns, the effect of the granulation process on the dissolution rate of the formulation was examined. Table 2 shows the API particle size, wetting agent and granulation process for formulas 1-3.
Table 2:
Figure GPA0000246715480000131
1. preparation method of formula 1
(1) Preparing materials: precisely weighing according to the prescription amount;
(2) sieving: mixing and sieving the materials except the magnesium stearate, wherein the model of a screen is 032R, and the rotating speed is 1440 rpm;
(3) mixing 1: adding the sieved material obtained in the step (2) into a mixing barrel, and mixing for 10min at the rotating speed of 10 rpm;
(4) and (3) mixing: sieving magnesium stearate with 30 mesh sieve, adding into the mixture obtained in step (3), rotating at 10rpm, and mixing for 5 min;
(5) and (3) granulating: and (4) adding the mixture obtained in the step (4) into a dry-method granulator, and after parameters are adjusted, starting granulation. The key process parameter settings are as follows: the rotating speed of the horizontal screw is 10-30 rpm, the rotating speed of the vertical screw is 250rpm, the rotating speed of the compression roller is 6rpm, the pressure of the compression roller is 20-30 bar, the distance between the compression rollers is 2mm, the transverse shallow grain compression roller is adopted, the crushing speed is 2000rpm, and the model of a screen is 0065;
(6) total mixing: sieving the added magnesium stearate with a 30-mesh sieve, adding the sieved magnesium stearate into the mixture obtained in the step 5, rotating at 10rpm, and mixing for 5 min;
(7) tabletting: tabletting the total mixed particles obtained in the step 6, wherein the weight of the tablets is 200mg, and the target hardness is 90N;
(8) coating: and (4) coating the plain tablets obtained in the step (7), wherein the coating weight is increased by 3.0%.
2. Preparation method of formula 2
(1) Preparing materials: precisely weighing according to the prescription amount shown in the table 1;
(2) preparing an adhesive: weighing the wetting agent according to the dosage of the povidone/wetting agent shown in table 2, dissolving the weighed apixaban and povidone into glacial acetic acid, and stirring to obtain a uniform solution for later use;
(3) and (3) granulating: adding anhydrous lactose, microcrystalline cellulose, croscarmellose sodium and sodium lauryl sulfate into a fluidized bed for preheating, spraying the binder solution obtained in the step (2), and starting granulation. Setting the atomization pressure to be 0.7Bar, the liquid spraying speed to be 7g/min, the material temperature to be 42 ℃, and setting the air inlet amount and the air inlet temperature according to the material fluidization state and the material temperature;
(4) straightening: finishing the dry particles obtained in the step (3), wherein the type of a screen is 032R;
(5) total mixing: adding additional magnesium stearate, and totally mixing the granules obtained in the step (4) at the rotation speed of 10rpm for 5 min;
(6) tabletting: tabletting the total mixed granules obtained in the step (5), wherein the weight of the tablets is 200mg, and the hardness is 90N;
(7) coating: and (4) coating the plain tablets obtained in the step (6), wherein the weight of the coating is increased by 3.0%.
3. Preparation method of formula 3
(1) Preparing materials: precisely weighing according to the prescription amount shown in the table 1;
(2) preparing an adhesive: weighing the wetting agent according to the dosage of the povidone/wetting agent shown in table 2, dissolving the weighed apixaban and povidone into glacial acetic acid, and stirring to obtain a uniform solution for later use;
(3) and (3) granulating: adding anhydrous lactose, microcrystalline cellulose, croscarmellose sodium and sodium dodecyl sulfate into a high-shear wet granulator, premixing for 5min, spraying the binder solution obtained in the step (2), controlling the spraying speed to be 5-60 g/min, and after the spraying is finished, starting granulation, wherein the granulation time is 3 min;
(4) and (3) drying: adding the wet particles obtained in the step (3) into a fluidized bed for drying, wherein the temperature of the materials at the end of drying is controlled at 50 ℃, and the LOD is controlled below 2%;
(5) straightening: finishing the dry particles obtained in the step (4), wherein the type of a screen is 032R;
(6) total mixing: adding additional magnesium stearate, and totally mixing the granules in the step (5) at the rotating speed of 10rpm for 5 min;
(7) tabletting: tabletting the total mixed granules obtained in the step (6), wherein the tablet weight is 200mg, and the target hardness is 90N;
(8) coating: and (4) coating the plain tablets obtained in the step (7), wherein the coating weight is increased by 3.0%.
4. Dissolution curve
Dissolution conditions
The method comprises the following steps: paddle method, 75 rpm;
dissolution medium: pH6.8 phosphate buffer solution + 0.05% Sodium Dodecyl Sulfate (SDS), 900 + -9 mL (DISTEK solvent preparation instrument degassing at 37 ℃ before use);
temperature of the medium: 37.0 plus or minus 0.5 ℃;
sampling time: 5. 10, 15, 20, 30, 45 and 60 min;
sampling volume: 2 mL;
sampling position: the distance from the top end of the paddle to the midpoint of the liquid level to the inner wall of the dissolution cup wall is 10 mm.
Chromatographic conditions
The instrument comprises the following steps: HPLC
Detection wavelength: UV280nm
A chromatographic column: agilent ZORBAX RX-C8, 4.6mm x 150mm, 5 μm
Or Welch Ultimate XB-C8, 4.6mm × 150mm, 5 μm
Mobile phase: (0.01mol/L potassium dihydrogen phosphate solution, pH adjusted to 3.8 with phosphoric acid) -acetonitrile (60: 40)
Column temperature: 25 deg.C
Flow rate: 1.0mL/min
Sample introduction amount: 80 μ L
Operating time: 6min (about 1.5 times the apixaban retention time).
Among them, Table 3 shows the dissolution curves (%)
Table 3: dissolution curves (%)
Prescription 5min 10min 15min 20min 30min 45min 60min
Prescription 1 12 18 23 28 31 32 32
Prescription 2 37 82 93 98 100 101 101
Prescription 3 33 64 90 93 97 99 100
And (4) conclusion: the formulas 2 and 3 adopt fluidized bed wet granulation and high shear wet granulation respectively, and the dissolution rate is obviously faster than that of the formula 1, 15min is already over 90 percent, and the dissolution platform is close to 100 percent as can be seen from the data in the table. Therefore, the wet granulation is suitable to be adopted, and the effect is optimal.
Example 2 wettingInvestigation of the kind of agent
In this example, the inventors measured the particle size D of apixaban90The influence of the wetting agent species on the dissolution rate of the formulation was examined at 92 μm. Table 4 shows the API particle size, wetting agent and granulation process for formulas 4-6.
Table 4:
Figure GPA0000246715480000151
1. preparation process of formula 4-6
(1) Preparing materials: precisely weighing according to the prescription amount shown in Table 1;
(2) preparing an adhesive: taking water, ethanol or glacial acetic acid according to the dosage of the povidone/wetting agent shown in the table 4, then dissolving the weighed apixaban and povidone into the wetting agent, and stirring for later use;
the subsequent steps are the same as the steps (3) - (7) in the preparation method of the prescription 2.
2. Dissolution curve
The dissolution conditions were the same as in example 1,
among them, Table 5 shows the dissolution curves (%) of the formulations 4 to 6,
table 5: dissolution curves (%)
Prescription 5min 10min 15min 20min 30min 45min 60min
Prescription 4 9 17 23 28 35 41 41
Prescription 5 8 15 22 27 34 39 40
Prescription 6 34 82 91 98 99 100 100
And (4) conclusion: from the prescription 4-6 adopting fluidized bed granulation, the prescription 6 adopts glacial acetic acid as a wetting agent, the dissolution rate is obviously faster than that of the prescription 4 and the prescription 5, and the dissolution platform is close to 100%; therefore, the glacial acetic acid is used as the wetting agent, the 15-min dissolution rate is greater than 90%, and the dissolution platform is normal and close to 100%, so that the glacial acetic acid is used as the wetting agent in the project, and the effect is optimal.
Meanwhile, the inventor also examines the dissolution rate of the composition obtained by taking DMSO as a wetting agent, and the inventor finds that the dissolution rate is fast by taking DMSO as the wetting agent and taking glacial acetic acid as the wetting agent.
EXAMPLE 3 examination of the amount of wetting agent
In this example, the inventors measured the particle size D of apixaban90Under the condition of 150 microns, the influence of the dose ratio of the povidone/glacial acetic acid on the dissolution rate of the preparation is examined. Wherein, Table 6 shows the API particle size, wetting agent and granulation process of formulas 7-11
Table 6:
Figure GPA0000246715480000161
1. preparation process of formula 7-11
(1) Preparing materials: precisely weighing according to the prescription amount shown in Table 1;
(2) preparing an adhesive: measuring glacial acetic acid according to the dosage of the povidone/glacial acetic acid shown in the table 6, dissolving the weighed apixaban and povidone in the glacial acetic acid, and stirring to obtain a uniform solution for later use;
the subsequent steps are the same as the steps (3) - (7) in the preparation method of the prescription 2.
3. Dissolution curve
The dissolution conditions were the same as in example 1
Among them, Table 7 shows the dissolution curves (%)
Table 7: dissolution curves (%)
Figure GPA0000246715480000162
Figure GPA0000246715480000171
And (4) conclusion: from the dissolution results of the prescription 7-11, the dissolution curves are similar, the dissolution in 15min is more than 85%, and the dissolution platform is normal and is close to 100%; therefore, when the content of the adhesive in the wetting agent is within the range of 0.02-0.5 g/mL, the product is quickly dissolved out, the dissolution platform is normal, and the quality standard is met. In addition. The inventors found that when the concentration of the binder in the wetting agent is less than 0.02g/mL, the amount of the binder solution is too large, the granulation time is significantly prolonged, time and energy are consumed, and the method is not suitable for industrial mass production, but the concentration of the binder is less than 0.02g/mL, which does not affect the quality of the obtained product; when the binder concentration is higher than 0.5g/mL, the solubility of the binder, such as povidone PVP, is limited, and part of the binder, such as PVP, is not dissolved and remains in suspension.
Example 4 particle size examination of API
1. Investigation of influence of API particle size on material cost
The active ingredient in the solid composition of apixaban claimed in the application adopts the particle diameter D90Apixaban of greater than 89 μm. And if the particle diameter D is adopted90When the apixaban solid composition is prepared by using the apixaban with the particle size of less than or equal to 89 mu m, the apixaban bulk drug needs to be crushed, and the material cost is greatly increased at the moment, which is specifically represented as follows: firstly, a pulverizer needs to be purchased, a universal pulverizer is generally selected, and the manufacturing cost is high; if the crude drug with very small particle size (such as less than or equal to 10 μm) is to be obtained, a jet mill needs to be purchased for micronization, which is more expensive. Secondly, the crushing process has large loss of the raw material medicines, the yield is generally between 80% and 90%, and more raw material medicines are consumed if sampling and full inspection are required to pass and stability is simultaneously inspected after crushing, so that the production cost is greatly increased; thirdly, the crushing process needs to consume a large amount of water, electricity and gas, the energy consumption is too high, and meanwhile, the operation by a plurality of people is also needed, and a large amount of time is also needed for installing equipment and cleaning equipment, so that more manpower and material resources are needed. Finally, the crushed raw material medicine is easy to agglomerate and needs to be used as the powder, so the crushed raw material medicine is not usedIs beneficial to the continuous production of commercialization. The attrition rates when API of different particle sizes was crushed are listed in table 8:
table 8:
particle size before pulverization Particle size after grinding Type of disintegrator Rate of loss of bulk drug
360 58 Universal pulverizer 10％
360 8 Pulverizer of jet mill 18％
150 30 Universal pulverizer 13％
150 4 Pulverizer of jet mill 20％
2.88kg of the raw material drug apixaban is consumed for producing one batch of registered products, if the raw material drug with the particle size of 10-89 mu m is used during the production of the drug, the raw material drug needs to be crushed by a universal crusher, the loss rate of the raw material drug is at least 10 percent, and at least 0.32kg of the raw material drug needs to be budgeted; and because sampling is needed to be carried out for detection in the crushing step and samples are appropriately reserved, the budget is 0.1 kg-0.5 kg (the dosage of 1-5 batches for each crushing and the sample reservation amount for each crushing are 0.5kg), if the energy consumption and the labor consumption in the crushing process are calculated, the cost of the raw material medicine is increased by at least 17% -31%, and the cost of equipment is not calculated. Similarly, it can be proved that if the raw material medicine with the particle size smaller than 10 μm is used, the cost of the raw material medicine is increased by 28-42% more sharply. As can be seen, the particle diameter D is used90The Apixaban bulk drug with the particle size of more than 89 mu m is granulated, so that the cost advantage is great.
2. Investigation of effect of API particle size on dissolution rate
In this example, the inventors examined the effect of different particle size API on the dissolution rate of the formulation under the condition that the amount of povidone/glacial acetic acid is 0.2 g/mL.
Table 9: API particle size, wetting agent and granulation process of formulas 2, 3, 6, 8, 12 and 13
Figure GPA0000246715480000181
Recipes 12 and 13 were prepared as follows:
(1) preparing materials: precisely weighing according to the prescription amount shown in the table 1;
(2) preparing an adhesive: measuring glacial acetic acid according to the dosage of the povidone/glacial acetic acid shown in the table 9, dissolving the weighed apixaban and povidone in the glacial acetic acid, and stirring to obtain a uniform solution for later use;
the subsequent steps are the same as steps (3) - (7) in the preparation method of the formula 2 or the steps (3) - (8) in the preparation method of the formula 3.
The dissolution conditions were the same as in example 1,
among them, Table 10 shows the dissolution curves (%) of recipes 2, 3, 6, 8, 12 and 13,
table 10: dissolution curves (%)
Prescription 5min 10min 15min 20min 30min 45min 60min
Prescription 2 37 82 93 98 100 101 101
Prescription 3 33 64 90 93 97 99 100
Prescription 6 34 82 91 98 99 100 100
Prescription 8 36 79 92 98 100 101 100
Prescription 12 39 85 97 98 98 99 98
Prescription 13 36 83 93 96 98 99 99
As can be seen from Table 10, the particle diameter D in API90On the premise of being larger than 89 mu m, the dissolution rate of the finished product reaches rapid dissolution no matter a wet granulation process or a fluidized bed granulation process is adopted, and the dissolution platform approaches 100%.
Example 5 stability study
In this example, the inventors examined the stability of the apixaban composition obtained by the preparation method of the example of the present invention. The specific method is as follows:
the Apixaban film-coated tablets are packaged by adopting HDPE bottles, a bag of 2g of silica gel drying agent is added in each bottle, 60 tablets are placed in each bottle, accelerated stability experiment investigation is carried out at 40 ℃/75% RH, and sampling is carried out for 0 day, 1 month, 2 months and 3 months to detect content, related substances and dissolution.
Extracting the processed Apixaban tablet with acetonitrile-ultrapure water (50: 50) solution, detecting with high performance liquid chromatograph, and calculating with external standard method. The dissolution detection adopts a USP first method paddle method for determination, adopts a high performance liquid chromatograph for detection, and adopts a main component external standard method for calculation. Thereby obtaining the content of the apixaban and the content of related substances in the processed apixaban tablets.
Apixaban content
Chromatographic conditions
The instrument comprises the following steps: high performance liquid chromatography (UV detector);
a chromatographic column: agilent ZORBAX RX-C8, 250mm × 4.6mm, 5 μm;
detection wavelength: 280 nm;
flow rate: 1.0 mL/min;
column temperature: 25 ℃;
sample introduction amount: 15 mu L of the solution;
operating time: 10min (about 1.5 times the apixaban main peak retention time);
content of related substance
Chromatographic conditions
The instrument comprises the following steps: high performance liquid chromatograph (UV detector)
A chromatographic column: agilent ZORBAX RX-C8, 4.6mm X250 mm, 5 μm;
detection wavelength: 280 nm;
flow rate: 1.0 mL/min;
column temperature: 20 ℃;
sample introduction amount: 10 mu L of the solution;
operating time: and (5) 48 min.
Wherein, Table 10 shows the content of Apixaban in formulas 2, 3, 6, 8, 12 and 13, and Table 11 shows the content of related substances in formulas 2, 3, 6, 8, 12 and 13
Table 10:
Figure GPA0000246715480000191
Figure GPA0000246715480000201
table 11:
Figure GPA0000246715480000202
Figure GPA0000246715480000211
accelerated stability test data show that the content of the preparation prepared by API with the particle size of more than 89 mu m is normal at each time point, and the fluctuation is small and very stable; compared with 0 day, the related substances are not obviously increased in three months, which indicates that the product quality is stable and controllable.
Example 6
On the premise of the preparation methods obtained in examples 1 to 4, the inventors further screened the prescription of the composition. The details are as follows:
recipe 14 and its preparation measurements are shown in table 12.
Table 12:
Figure GPA0000246715480000212
Figure GPA0000246715480000221
wherein the particle size of the apixaban is 150 mu m
Weighing glacial acetic acid according to the concentration of the povidone of 22.5 percent (g/mL), sequentially adding the apixaban bulk drug with the particle size of 150 mu m and the povidone into the glacial acetic acid, and stirring the mixture to dissolve the apixaban bulk drug and the povidone to obtain the adhesive solution. Adding anhydrous lactose, microcrystalline cellulose, croscarmellose sodium and sodium lauryl sulfate into a fluidized bed, preheating, and spraying liquid when the material temperature reaches 42 ℃. And drying after the spraying is finished until the LOD and the acetic acid residue of the product are lower than the quality standard. The obtained dry granules were subjected to size reduction with a 032R mesh, followed by addition of magnesium stearate for total mixing and tableting. Coating the obtained plain tablets to obtain the target product.
Recipe 15 and its preparation variables are shown in Table 13.
Table 13:
Figure GPA0000246715480000222
wherein the particle size of the apixaban is 200 mu m
Weighing glacial acetic acid according to the concentration of the povidone of 22.5 percent (g/mL), sequentially adding the apixaban bulk drug with the particle size of 200 mu m and the povidone into the glacial acetic acid, and stirring the mixture to dissolve the apixaban bulk drug and the povidone to obtain the adhesive solution. Adding anhydrous lactose, microcrystalline cellulose, croscarmellose sodium and sodium lauryl sulfate into a fluidized bed for preheating, and starting to spray liquid when the temperature of the materials reaches 42 ℃. And drying after the spraying is finished until the LOD and the acetic acid residue of the product are lower than the quality standard. The obtained dry granules were subjected to size reduction with a 032R mesh, followed by addition of magnesium stearate for total mixing and tableting. Coating the obtained plain tablets to obtain the target product.
Prescription 16 andthe preparation weighing amounts are shown in table 14.
Table 14:
Figure GPA0000246715480000231
wherein the particle size of the apixaban is 200 mu m
Weighing glacial acetic acid according to the concentration of 20% (g/mL) of the povidone, sequentially adding the apixaban bulk drug with the particle size of 200 mu m and the povidone into the glacial acetic acid, and stirring the mixture to dissolve the apixaban bulk drug and the povidone to obtain the adhesive solution. Adding anhydrous lactose, microcrystalline cellulose, croscarmellose sodium and sodium lauryl sulfate into a fluidized bed for preheating, and starting to spray liquid when the temperature of the materials reaches 42 ℃. And drying after the spraying is finished until the LOD and the acetic acid residue of the product are lower than the quality standard. The obtained dry granules were subjected to size reduction with a 032R mesh, followed by addition of magnesium stearate for total mixing and tableting. Coating the obtained plain tablets to obtain the target product.
Recipe 17 and its preparation measurements are shown in Table 15.
Table 15:
Figure GPA0000246715480000232
Figure GPA0000246715480000241
wherein the particle size of the apixaban is 200 mu m
Weighing glacial acetic acid according to the concentration of the povidone of 15 percent (g/mL), sequentially adding the apixaban bulk drug with the particle size of 200 mu m and the povidone into the glacial acetic acid, and stirring the mixture to dissolve the apixaban bulk drug and the povidone to obtain the adhesive solution. Adding anhydrous lactose, microcrystalline cellulose, croscarmellose sodium and sodium lauryl sulfate into a fluidized bed for preheating, and starting to spray liquid when the temperature of the materials reaches 42 ℃. And drying after the spraying is finished until the LOD and the acetic acid residue of the product are lower than the quality standard. The obtained dry granules were subjected to size reduction with a 032R mesh, followed by addition of magnesium stearate for total mixing and tableting. Coating the obtained plain tablets to obtain the target product.
Recipe 18 and its preparation measurements are shown in table 16.
Table 16:
Figure GPA0000246715480000242
Figure GPA0000246715480000251
the particle size of the Apixaban is 300 mu m
Weighing glacial acetic acid according to the concentration of the povidone of 22.5 percent (g/mL), sequentially adding apixaban bulk drug with the particle size of 89 mu m and the povidone into the glacial acetic acid, and stirring the mixture to dissolve the apixaban bulk drug and the povidone to obtain the adhesive solution. Adding anhydrous lactose, microcrystalline cellulose, croscarmellose sodium and sodium lauryl sulfate into a fluidized bed for preheating, and starting to spray liquid when the temperature of the materials reaches 42 ℃. And drying after the spraying is finished until the LOD and the acetic acid residue of the product are lower than the quality standard. The obtained dry granules were subjected to size reduction with a 032R mesh, followed by addition of magnesium stearate for total mixing and tableting. Coating the obtained plain tablets to obtain the target product.
In this example, the inventors investigated the properties of the apixaban tablets obtained in example 6.
1. Dissolution test
The dissolution conditions were the same as in example 1, and Table 17 shows dissolution curves (%)
Table 17: dissolution curves (%). of formulas 14 to 18
Prescription 5min 10min 15min 20min 30min 45min 60min
Prescription 14 38 81 94 98 98 99 98
Prescription 15 39 85 97 98 98 99 98
Prescription 16 37 82 93 98 100 101 101
Prescription 17 33 64 90 93 97 99 100
Prescription 18 41 83 96 101 101 102 102
2. Stability test
Table 18: stability data for prescription 18
Figure GPA0000246715480000252
Figure GPA0000246715480000261
As can be seen from tables 17 and 18, the apixaban tablets prepared by the preparation schemes obtained by screening and optimizing in examples 1 to 4 have good stability and high dissolution rate, such as formula 14 to 18, and the dissolution rate can be greater than or equal to 90% in 15 min.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (23)

1. The solid composition of apixaban is characterized by comprising apixaban, wherein the particle size D of the apixaban90Greater than 89 μm, further comprising a binder, a filler, a disintegrant, a surfactant, and a lubricant; the solid composition of apixaban is obtained by wet granulation by: dissolving apixaban and a binder in a wetting agent to obtain a binder solution; the adhesive is povidone, and the wetting agent is acetic acid; the content of the adhesive in the acetic acid is 0.02g/mL-0.5 g/mL; the filler is corn starch, pregelatinized starch, composite starch, anhydrous lactose, lactose monohydrate, microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, mannitol, maltitol, inositol, xylitol, lactitol or any combination thereof; the disintegrant is sodium carboxymethyl starch, crospovidone, croscarmellose sodium, sodium croscarmellose, low-substituted hydroxypropyl cellulose or any combination thereof; the surfactant is sodium dodecyl sulfate, sodium dodecyl sulfonate, tween, span or their mixtureAny combination; the lubricant is stearic acid, magnesium stearate, calcium stearate, zinc stearate, palmitoyl glyceryl stearate, sodium stearyl fumarate, canola oil, hydrogenated vegetable oil, mineral oil sodium lauryl sulfate, magnesium oxide, silica gel micropowder, silicone oil, polyethylene glycol, polyvinyl alcohol, sodium benzoate, talcum powder or any combination thereof; based on the total weight of the solid composition, the content of the binder is 2.00-8.00%, the content of the disintegrant is 2.00-8.00%, the content of the surfactant is 0.50-4.00%, and the content of the lubricant is 0.50-2.50%.
2. Solid composition according to claim 1, characterized in that the particle size D of the apixaban90Not less than 100 μm and not more than 550 μm.
3. The solid composition according to claim 1, characterized in that the filler is a mixture of anhydrous lactose and microcrystalline cellulose.
4. The solid composition according to claim 3, characterized in that the content of anhydrous lactose is 33.50-63.50% and the content of microcrystalline cellulose is 24.00-54.00% based on the total weight of the solid composition.
5. The solid composition according to claim 1, characterized in that the disintegrant is croscarmellose sodium.
6. The solid composition of claim 1, wherein the surfactant is sodium lauryl sulfate.
7. The solid composition of claim 1, wherein the lubricant is magnesium stearate.
8. A solid composition of apixaban, characterized in that,
comprises the following steps: 2.50 parts by weight of apixaban, 33.50-63.50 parts by weight of anhydrous lactose, 24.00-54.00 parts by weight of microcrystalline cellulose, 2.00-8.00 parts by weight of croscarmellose sodium, 2.00-8.00 parts by weight of povidone, 0.50-4.00 parts by weight of sodium lauryl sulfate and 0.50-2.50 parts by weight of magnesium stearate, wherein the particle size D of the apixaban is90Greater than 89 μm; the solid composition of apixaban is obtained by wet granulation by: apixaban and the binder povidone were dissolved in the wetting agent acetic acid to obtain a binder solution.
9. The solid composition according to claim 8, wherein the particle size D of apixaban is such that90Not less than 100 μm and not more than 550 μm.
10. Solid composition of apixaban, characterized in that it comprises, based on the total weight of the solid composition: 2.50% apixaban, 48.50% anhydrous lactose, 39.00% microcrystalline cellulose, 4.00% croscarmellose sodium, 3.00% povidone, 2.00% sodium lauryl sulfate and 1.00% magnesium stearate, the particle size D of the apixaban90Greater than 89 μm; the solid composition of apixaban is obtained by wet granulation by: apixaban and the binder povidone were dissolved in the wetting agent acetic acid to obtain a binder solution.
11. Solid composition of apixaban, characterized in that it comprises, based on the total weight of the solid composition: 2.50% apixaban, 63.50% anhydrous lactose, 24.00% microcrystalline cellulose, 4.00% croscarmellose sodium, 3.00% povidone, 2.00% sodium lauryl sulfate and 1.00% magnesium stearate, the particle size D of the apixaban90Greater than 89 μm; the solid composition of apixaban is obtained by wet granulation by: mixing ApixateThe executive and binder povidone are dissolved in the wetting agent acetic acid in order to obtain a binder solution.
12. Solid composition of apixaban, characterized in that it comprises, based on the total weight of the solid composition: 2.50% apixaban, 33.50% anhydrous lactose, 54.00% microcrystalline cellulose, 4.00% croscarmellose sodium, 3.00% povidone, 2.00% sodium lauryl sulfate and 1.00% magnesium stearate, the particle size D of the apixaban90Greater than 89 μm; the solid composition of apixaban is obtained by wet granulation by: apixaban and the binder povidone were dissolved in the wetting agent acetic acid to obtain a binder solution.
13. Solid composition of apixaban, characterized in that it comprises, based on the total weight of the solid composition: 2.50% of apixaban, 47.50% of anhydrous lactose, 39.00% of microcrystalline cellulose, 2.00% of croscarmellose sodium, 8.00% of povidone, 0.50% of sodium dodecyl sulfate and 0.50% of magnesium stearate, wherein the particle size D of the apixaban is90Greater than 89 μm; the solid composition of apixaban is obtained by wet granulation by: apixaban and the binder povidone were dissolved in the wetting agent acetic acid to obtain a binder solution.
14. Solid composition of apixaban, characterized in that it comprises, based on the total weight of the solid composition: 2.50% apixaban, 42.00% anhydrous lactose, 39.00% microcrystalline cellulose, 8.00% croscarmellose sodium, 2.00% povidone, 4.00% sodium lauryl sulfate and 2.50% magnesium stearate, the particle size D of the apixaban90Greater than 89 μm; the solid composition of apixaban is obtained by wet granulation by: dissolving Apixaban and adhesive povidone in wetting agent acetic acid to obtainA binder solution.
15. The solid composition according to any one of claims 1 to 14, wherein the solid composition is a tablet, capsule or granule.
16. A method of preparing the composition of any one of claims 1 to 15, comprising:
adding the filler, the disintegrant and the surfactant into a fluidized bed and carrying out preheating treatment;
spraying the binder solution into the pre-heat treated product;
subjecting the pre-heat-treated product sprayed with the binder solution to a drying treatment so as to obtain dry particles;
subjecting the dry granules to a size reduction treatment; and
adding a lubricant to the granules obtained after the size stabilization and carrying out total mixing treatment.
17. The method of claim 16, wherein the temperature after the pre-heat treatment is from 35 ℃ to 50 ℃.
18. The method of claim 16, wherein the spraying is performed at an atomization pressure of 0.5bar to 2.0bar and a spray velocity of 3.0g/min to 20.0 g/min.
19. A method of preparing the composition of any one of claims 1 to 15, comprising:
adding the filler, the disintegrant and the surfactant into a high-shear wet granulator and performing premixing treatment;
spraying the binder solution into the pre-mixed treated product so as to obtain wet granules;
adding the wet granules into a fluidized bed for drying treatment so as to obtain dry granules;
subjecting the dry granules to a size reduction treatment; and
adding a lubricant to the granules obtained after the size stabilization and carrying out total mixing treatment.
20. The method of claim 19, wherein the spraying is performed at a spray velocity of 5g/min to 60 g/min.
21. The method of claim 16 or 19, further comprising compressing and coating the total blended product.
22. A process for preparing an apixaban composition comprising:
(1) dissolving apixaban and a binder in a wetting agent so as to obtain a binder solution, wherein the particle size D90 of the apixaban is more than 89 μm, the wetting agent is acetic acid, the binder is povidone, and the content of the binder in the wetting agent is 0.02g/mL-0.5 g/mL;
(2) adding anhydrous lactose as filler, microcrystalline cellulose, croscarmellose sodium as disintegrant and sodium lauryl sulfate as surfactant into a fluidized bed, and preheating at 35-50 deg.C;
(3) spraying the binder solution into the pre-heated product under conditions of an atomization pressure of 0.5bar to 2.0bar and a spray velocity of 3.0g/min to 20.0g/min, and drying the pre-heated product sprayed with the binder solution to obtain dry particles;
(4) subjecting the dry granules to a size reduction treatment;
(5) adding magnesium stearate serving as a lubricant into granules obtained after finishing and carrying out total mixing treatment; and
(6) performing tabletting and coating treatment on the product after the total mixing treatment;
wherein, based on the total weight of the composition, the content of the adhesive is 2.00-8.00%, the content of anhydrous lactose is 33.50-63.50%, the content of microcrystalline cellulose is 24.00-54.00%, the content of the disintegrant is 2.00-8.00%, the content of the surfactant is 0.50-4.00%, and the content of the lubricant is 0.50-2.50%.
23. A process for preparing an apixaban composition comprising:
(1) dissolving apixaban and a binder in a wetting agent in order to obtain a binder solution, said apixaban having a particle size D90More than 89 μm, the wetting agent is acetic acid, the adhesive is povidone, and the content of the adhesive in the wetting agent is 0.02g/mL-0.5 g/mL;
(2) adding anhydrous lactose as filler, microcrystalline cellulose, croscarmellose sodium as disintegrant and sodium lauryl sulfate as surfactant into a high-shear wet granulator, and premixing;
(3) spraying the binder solution into the product after the pre-mixing treatment, wherein the spraying is carried out at a spraying speed of 5 g/min-60 g/min, and granulating the product after the pre-mixing treatment sprayed with the binder solution for 3 min-5 min so as to obtain wet granules;
(4) adding the wet granules into a fluidized bed for drying treatment so as to obtain dry granules;
(5) subjecting the dry granules to a size reduction treatment;
(6) adding magnesium stearate serving as a lubricant into granules obtained after finishing and carrying out total mixing treatment; and
(7) performing tabletting and coating treatment on the product after the total mixing treatment;
wherein, based on the total weight of the composition, the content of the adhesive is 2.00-8.00%, the content of anhydrous lactose is 33.50-63.50%, the content of microcrystalline cellulose is 24.00-54.00%, the content of the disintegrant is 2.00-8.00%, the content of the surfactant is 0.50-4.00%, and the content of the lubricant is 0.50-2.50%.
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